A Novel and Efficient Synthesis of a Highly Active Analogue of clasto-Lactacystin β-Lactone

Herein, we describe a new convergent synthesis of a more potent analogue of clasto-lactacystin β-lactone (2), PS-519 compound 4, which is currently in preclinical development for the treatment of ischemia−reperfusion injury in stroke and myocardial infarction. The synthetic strategy relies on buildi...

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Bibliographic Details
Published in:Journal of the American Chemical Society 1999-11, Vol.121 (43), p.9967-9976
Main Authors: Soucy, François, Grenier, Louis, Behnke, Mark L, Destree, Antonia T, McCormack, Teresa A, Adams, Julian, Plamondon, Louis
Format: Article
Language:English
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Summary:Herein, we describe a new convergent synthesis of a more potent analogue of clasto-lactacystin β-lactone (2), PS-519 compound 4, which is currently in preclinical development for the treatment of ischemia−reperfusion injury in stroke and myocardial infarction. The synthetic strategy relies on building two intermediates (an oxazoline and an aldehyde) which are joined through a doubly diastereoselective aldol reaction, setting up the requisite unichiral centers in the final product (4). The facial selectivity and ultimate stereocontrol are achieved by employing a trivalent aluminum Lewis acid, Me2AlCl, in a chelation-induced reaction which yields a single aldol adduct. The efficiency of the synthetic approach has allowed for the preparation of multigram quantities of clinical grade material, which will support Phase I studies.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja991175f